Diastereoselective synthesis of 6-trifluoromethyl-5,6-dihydropyrans via phosphine-catalyzed [4+2] annulation of α-benzylallenoates with ketones

Article abstract of DOI:10.1021/ol101762z

The highly diastereoselective synthesis of 6-trifluoromethyl-5,6- dihydropyrans was realized by the phosphine-catalyzed [4 + 2] annulation of ethyl α-benzylallenoates and trifluoromethyl ketones.

Full text of DOI:10.1021/ol101762z

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4168-4171
Diastereoselective Synthesis of
6-Trifluoromethyl-5,6-dihydropyrans via
Phosphine-Catalyzed [4 + 2] Annulation
of r-Benzylallenoates with Ketones
Tong Wang and Song Ye*
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
songye@iccas.ac.cn
Received July 29, 2010
ABSTRACT
The highly diastereoselective synthesis of 6-trifluoromethyl-5,6-dihydropyrans was realized by the phosphine-catalyzed [4 + 2] annulation of
ethyl r-benzylallenoates and trifluoromethyl ketones.
Substituted pyrans and dihyropyrans present important
structural motifs in a number of biologically active com-
pounds and natural products.1 Among the many methods
developed, the hetero-Diels-Alder (HDA) reaction of a diene
or its analogue with carbonyl compound remains one of the
most powerful tools for the synthesis of these six-membered
heterocycles.2,3 However, electron-rich dienes are generally
required for the HDA reaction, which limit the scope of
accessible dihydropyrans. Thus, the construction of dihyro-
pyrans from diene or its analogues with diverse substituents,
especially those with electron-withdrawing groups, are still
highly desired.
deficient alkynes catalyzed by a tertiary phosphine, such as the
isomerizations of alkynes to conjugated dienes5 and the um-
polung addition to R- or γ-carbon of allenoates and butynoates.6
(3) For recent examples of the synthesis of pyran derivatives, see: (a)
Barroso, S.; Blay, G.; Mun˜oz, M. C.; Pedro, J. R. AdV. Synth. Catal. 2009,
351, 107. (b) Zhao, S.-L.; Zheng, C.-W.; Wang, H.-F.; Zhao, G. AdV. Synth.
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Estrella-Jimenez, M.; Ghiviriga, I.; Wright, D. L. Angew. Chem., Int. Ed.
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Organophosphorous compounds have been demonstrated
successfully as nucleophilic catalysts (Lewis base catalysts) for
a wide variety of reactions.4 In early 1990s, Trost et al. and Lu
et al. independently developed a series of reactions of electron
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10.1021/ol101762z  2010 American Chemical Society
Published on Web 08/16/2010

In 1995, Lu et al. published the pioneering triphenylphosphine-
catalyzed [3 + 2] annulation of allenoates with electron-deficient
olefins for the synthesis of cyclopentenes.7-9 Soon after, the
reaction was successfully expanded to N-tosylimines to
furnish pyrroline efficiently.10
Scheme 1
.
Phosphine-Catalyzed/Mediated Reactions of
R-Alkylallenoates
Ten years later, Kwon et al. reported a novel [4 + 2]
annulation of R-alkyl allenoates11 with imines to afford
tetrahydropyridines,12 followed by the reaction of R-alkyl-
allenoate with electron-deficient olefins to give cyclohexenes
(Scheme 1, reactions a and b).13 Interestingly, a [3 + 2]
annulation was found for the phosphine- and water-cocata-
lyzed reaction of R-methylallenoates with fumarates by Yu
et al. (reaction c).14 In contrast to imines and olefins, the
phosphine-catalyzed reaction of R-alkylallenoate with car-
(6) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (b)
Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (c) Trost, B. M.;
Dake, G. R. J. Org. Chem. 1997, 62, 5670. (d) Alvarez-Ibarra, C.; Csa´ky¨,
A. G.; Go´mez de la Oliva, C. Tetrahedron Lett. 1999, 40, 8465. (e) Alvarez-
Ibarra, C.; Csa´ky¨, A. G.; Go´mez de la Oliva, C. J. Org. Chem. 2000, 65,
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J. Am. Chem. Soc. 1997, 119, 7595. (h) Lu, C.; Lu, X. Org. Lett. 2002, 4,
bonyl compounds has been hardly reported.15 During the
preparation of this manuscript, Kwon et al. and He et al.
independently reported several interesting reaction modes for
the phosphine-mediated reaction of R-substituted allenoates
with aldehydes to give dienes16 or cyclopropanes17 (reactions
d and e) instead of [4 + 2] cycloadducts. These reports
prompted us to disclose our results of the phosphine-
catalyzed [4 + 2] annulation of R-benzyl allenoates with
trifluoromethylketones to afford the desired dihydropyrans
(reaction f).
Trifluoromethyl ketones, which are active enough and have
wide applications in the synthesis of valuable fluorinated
compounds,18,19 were tested as the potential substrate. To
our delight, in the presence of 20 mol % of triphenylphos-
phine, R-benzyl allenoate (1a) and trifluoromethyl(phe-
nyl)ketone (2a) could react slowly in refluxing dichlo-
romethane to give the corresponding cycloadduct 3aa in 72%
isolated yield of pure cis-isomer with highly diastereoselec-
tivity of the reaction mixture (cis/trans ) 14:1) (Table 1,
entry 1).
4677
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Solvent screening revealed that dichloromethane is the
solvent of choice, while other chlorinated solvents such as
chloroform and 1,2-dichloroethane gave decreased yields and
diastereoselectivities (entries 1-3). The reaction in toluene
or THF went extremely slowly, giving only trace product
even after 4 days (entries 4 and 5). Reaction in ethanol or
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(14) Liang, Y.; Liu, S.; Yu, Z.-X. Synlett 2009, 905.
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with aldehydes was reported: Xu, S.; Zhou, L.; Ma, R.; Song, H.; He, Z.
Chem.sEur. J. 2009, 15, 8698.
(11) For selected metal-catalyzed reaction of R-alkylallenoates, see: (a)
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Zhu, J.; Cheng, Z.; Xie, H.; Li, S.; Wu, Y. Org. Lett. 2010, 12, 2434. (c)
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4716. (b) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686. (c) Tran,
Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (d) Castellano, S.; Fiji, H. D. G.;
Kinderman, S. S.; Watanabe, M.; Pablo de, Leon; Tamanoi, F.; Kwon, O.
J. Am. Chem. Soc. 2007, 129, 5843. For a catalytic asymmetric reaction,
see: (e) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
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(19) We recently reported a N-heterocyclic carbene-catalyzed reaction
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.
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Org. Lett., Vol. 12, No. 18, 2010
4169

Table 1. Optimization of Conditions
Table 2. Synthesis of Dihydropyrans through PPh3-Catalyzed
Annulation of Allenoates and Ketones
additive
(20 mol %)
entry
PR3
Ph3P
solvent
dra
yield (%)b
yield
(%)b
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
DCE
toluene
THF
14:1
9:1
7:1
ND
ND
7:1
6:1
11:1
13:1
72
41
45
trace
trace
16
20
58
63
59
61
trace
trace
76
no.
1 (R)
1a (Ph)
1b (4-MeC6H4)
1c (4-MeOC6H4) 2a (Ph, CF3)
1d (4-BrC6H4)
1e (3-BrC6H4)
1f (2-BrC6H4)
1g (2-MeC6H4)
1h (H)
2 (R′, R′′)
2a (Ph, CF3)
3
dra
14:1 76
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
n-Bu3P
1
2
3
4
5
6
7
8
9
3aa
2a (Ph, CF3)
3ba 15:1 75
3ca 14:1 67
3da 18:1 69
EtOH
EtOAc
2a (Ph, CF3)
2a (Ph, CF3)
2a (Ph, CF3)
2a (Ph, CF3)
2a (Ph, CF3)
2a (Ph, CF3)
2b (4-MeC6H4, CF3)
3ea
3fa
3ga
3ha
3ia
13:1 65
14:1 85
12:1 68
CH2Cl2 H2O
CH2Cl2 MeOH
CH2Cl2 C6H5COOH 17:1
9
10
11
12
13
14c
NR
trace
3ab 11:1 66
10:1 53
3ad >25:1 85
CH2Cl2
6:1
1i (CO2Et)
(R)-BINAP CH2Cl2
(+)-DIOP
Ph3P
ND
ND
14:1
10 1a (Ph)
11 1a (Ph)
12 1a (Ph)
13 1a (Ph)
14 1a (Ph)
15 1a (Ph)
16 1a (Ph)
17 1a
CH2Cl2
CH2Cl2
2c (4-MeOC6H4, CF3) 3ac
2d (4-ClC6H4, CF3)
2e (2-thienyl, CF3)
2f (Ph, C2F5)
2g (Ph, CO2Me)
2h (Ph, CN)
a Determined by 1H NMR (300 MHz) of the reaction mixture. b Isolated
yield of pure cis-isomer. c 2.0 equiv of 2a was utilized. BINAP ) 2,2′-
bis(diphenylphosphino)-1,1′-binaphthalene; DIOP ) 1,4-bis(diphenylphos-
phino)-2,3-O-isopropylidene-2,3-butanediol. ND ) not determined.
3ae
3af
3ag
3ah
3ai
13:1 58
8:1 44
NR
NR
NR
2i N-methylisatin
a Determined by 1H NMR (300 MHz) of the reaction mixture. b Isolated
yield of pure cis-isomer. NR ) No reaction.
ethyl acetate offered cycloadduct in low yield (entries 6 and
7). In view of the possible acceleration effect of trace water
in the phosphine-catalyzed reactions,20 20 mol % of water,
methanol, or benzoic acid was added to the reaction.
However, no notable acceleration was observed for these
reactions with protonic additives (entris 8-10).
Except for triphenylphosphine, tributylphosphine also
worked well for catalyzing the reaction albeit in somewhat
low yield (entry 11). Unfortunately, reactions catalyzed by
two chiral organophosphines (R)- BINAP and (+)-DIOP
went extremely slowly and gave only trace cycloadduct after
3 days (entries 12 and 13).
With the optimized reaction conditions in hand, a variety of
R-alkyl allenoates and ketones were then examined for the
phosphine-catalyzed [4 + 2] annulation (Table 2). It was found
that R-benzyl allenoates both with an electron-donating and with
an electron-withdrawing substituent (1b-d, R ) 4-MeC6H4,
4-MeOC6H4, 4-BrC6H4) worked well to furnish the correspond-
ing dihydropyrans in good yields with high diastereoselectivities
(entries 2-4). R-Benzyl allenoates with a meta- or ortho-
substituent (1e-g, R ) 3-BrC6H4, 2-BrC6H4, 2-MeC6H4)
showed comparable results as with a para-substituent (entries
5-7). Unfortunately, R-methyl or R-ethoxylcarbonyl allenoate
(1h,i, R ) H, CO2Et) gave no or only trace corresponding [4
+ 2] annulation product (entries 8 and 9).
ketone 2d with an electron-withdrawing group (R′ )
4-ClC6H4) reacted smoothly with allenoate 1a to furnish the
desired dihydropyrans in good yields with high diastereo-
selectivities (entries 10-12). The ketone 2e with a heteroaryl
group (R′ ) 2-thienyl) also worked well (entry 13). Penta-
fluoroethyl(phenyl)ketone 2f afforded the corresponding
dihydropyran in somewhat low yield with good diastereo-
selectivity (entry 14). However, no cycloadduct was found
for the reaction of methyl 2-oxo-2-phenylacetate (2 g),
benzoyl cyanide (2h), and N-methylisatin (2i) under current
reaction conditions (entries 15-17).
Except for its potential biological activity, the resulted
highly functionalized dihydropyrans also provide an op-
portunity for useful chemical transformations. For example,
reduction of the dihydropyran 3aa with hydrogen to give
corresponding tetrahydropyran 4aa in high yield with
exclusive diastereoselectivity (eq 1).21
Both the trifluoromethyl(aryl)ketones 2b,c with an electron-
donating substitutent (R′ ) 4-MeC6H4, 4-MeOC6H4) and
(20) (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.;
Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (b) Liang,
Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem.sEur. J. 2008, 14, 4316. (c)
Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Tetrahedron
Lett. 2007, 48, 3617.
The structure and relative configuration of dihydropyran
3ea was unambiguously established by the X-ray analysis
of its crystal (Figure 1).
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Org. Lett., Vol. 12, No. 18, 2010

Figure 1. X-ray structure of dihydropyran 3ea.
Figure 2. Possible catalytic cycle.
fluoromethyl ketones. Thus, it demonstrated that, in contrast
to the reported olefination and cyclopropanation reactions
of R-alkylallenoate with aldehydes, [4 + 2] annulation is
also possible for the phosphine-catalyzed reaction of R-alkyl-
allenoates with electron-deficient ketones.
The highly functionalized fluorinated dihydropyrans may
find applications in medicinal and synthetic chemistry. The
asymmetric [4 + 2] annuations of R-alkylallenoates with
ketones and other related reactions are underway in our
laboratory.
This phosphine-catalyzed [4 + 2] annulation of R-benzy-
lallenoates and ketones is expected to go with a similar
catalytic cycle as proposed by Kwon et al. (Figure 2).12a,13
The nucleophilic addition of triphenylphosphine to allene 1
gives an allylic zwitterion A. The sterically favored γ-ad-
dition of the zwitterion A to ketone 2 leads to R,ꢀ-unsaturated
ester B, which may equilibrate with R,ꢀ′-unsaturated ester
C by several proton transfer processes. The intramolecular
SN′ substitution in a 6-endo cyclization mode furnishs
dihydropyran 3 and regenerates the catalyst.
It is worth noting that no olefination or cyclopropanation
product is observed in our reaction,16,17 which is possible
due to the thermodynamical and kinetical disfavor of the
olefination or cyclopropanation reactions with more sterically
demanded ketones instead of aldehydes.
In conclusion, a series of 3-ethoxylcarbonyl-2,6-diaryl-6-
trifluoromethyl-5,6-dihydropyrans were synthesized with
highly diastereoselectivities through the phosphine-catalyzed
[4 + 2] annulation of ethyl R-benzylallenoates and tri-
Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (No. 20872143, 20932008),
the Ministry of Science and Technology of China (2009ZX-
5909501-018), and the Chinese Academy of Sciences is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, compound characteriations, and crystal structure data
of dihydropyran 3ea in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) The relative stereochemistry of 4aa was assigned by the coupling
constants and NOE ananlysis of its NMR spectra.
OL101762Z
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